Adult nerves of the mammalian central nervous system (CNS) show poor regenerative ability after axonal injury. Spontaneous growth of injured axons does occur, but ceases after a few hundred microns without traversing the site of the injury and elongating in the distal stump. The failure to regenerate has been attributed to the inhospitable nature of the nerve's environmental milieu, including the inability of astrocytes (the scar-forming cells) to support growth, the paucity of macrophages and/or their products, and the formation of mature oligodendrocytes which inhibit axonal growth.
We recently showed that in a spontaneously regenerating system, e.g., adult fish optic nerve, both the response to injury and the process of regeneration are associated with the presence of a factor(s), that we designated oligodendrocyte cytotoxic factor (OCF), which is selectively cytotoxic to oligodendrocytes of both fish and rats (Published European Application EP No. 415321; Cohen et. al., 1990; Sivron et al., 1991). This fish-derived factor was later identified by us as an IL-2-like molecule, with a molecular weight of 28 kDa as compared to 15 kDa in human immune IL-2 and 14 kDa in fish lymphocyte-derived IL-2 (Published European Application EP No. 501445; Eitan et al., 1992). This difference in molecular weight between OCF and IL-2 raised questions with regard to the origin of the factor, i.e., whether it is locally modified IL-2--derived from resident cells in the nerve or from inflammatory cells--or the product of a gene distinct from the gene encoding for immune IL-2 but sharing high homology with it.
It has now been found according to the present invention that an enzyme, identified as a member of the transglutaminase family and found at elevated levels after optic nerve injury in the fish but not in mammals, plays a role in modifying IL-2, possibly by cross-linkage of two molecules, in such a was as to produce the high molecular weight IL-2-like substance observed in the injured fish optic nerve. This new nerve-derived transglutaminase, herein designated TG.sub.N, causes dimerization of IL-2, thereby rendering it cytotoxic to oligodendrocytes.